Downregulation of the Long Non-Coding RNA <i>MDL1AS</i> Alters Metabolism, Differentiation, and Radiosensitivity in NTERA2 and SH-SY5Y Cells

<b>Background/Objectives</b>: Non-coding RNAs provide new chances of targeting multiple oncogenic pathways. Many long non-coding RNAs (lncRNAs) are being characterized as relevant in cancer initiation, progression, and recurrence. <i>Mitochondrial D-loop 1 antisense lncRNA (MDL1AS)</i> is a novel lncRNA that might be important in cancer development, so the aim of this project was to understand its function in differently differentiated cancer cells. <b>Methods</b>: The effects of <i>MDL1AS</i> downregulation on the cellular behavior of NTERA2 and SH-SY5Y cell lines were studied. <b>Results</b>: <i>MDL1AS</i> reduction inhibited oxidative phosphorylation in NTERA2 cells and induced neuritic differentiation in SH-SY5Y cells. This downregulation also produced a strong DNA damage response (DDR) and an increased apoptotic signature by RNAseq analysis, and decreased proliferation in both cell lines. It also decreased radiosensitivity in NTERA2 cells but not in SH-SY5Y. <b>Conclusions</b>: These results suggest that <i>MDL1AS</i> reduction can modulate radiosensitivity, metabolism, and differentiation in a cell type-specific manner. Furthermore, <i>MDL1AS</i> may constitute a predictive biomarker and a molecular target for new therapies.